Method for administering omega-conopeptide

ABSTRACT

The present invention is directed to a method of producing analgesia in a mammalian subject. The method includes administering to the subject an omega conopeptide, preferably ziconotide, in combination with an analgesic selected from the group consisting of morphine, bupivacaine, clonidine, hydromorphone, baclofen, fentanyl l, buprenorphine, and sufentanil, or its pharmaceutically acceptable salts thereof, wherein the ω-conopeptide retains its potency and is physically and chemically compatible with the analgesic compound. A preferred route of administration is intrathecal administration, particularly continuous intrathecal infusion. The present invention is also directed to a pharmaceutical formulation comprising an omega conopeptide, preferably ziconotide, an antioxidant, in combination with an analgesic selected from the group consisting of morphine, bupivacaine, clonidine, hydromorphone, baclofen, fentanyl, buprenorphine, and sufentanil.

This application is a divisional of U.S. application Ser. No.15/651,655, filed Jul. 17, 2017; which is a continuation of U.S.application Ser. No. 14/788,524, filed Jun. 30, 2015, now U.S. Pat. No.9,707,270; which is a continuation of U.S. application Ser. No.14/310,533, filed Jun. 20, 2014; which is a continuation of U.S.application Ser. No. 14/133,303, filed Dec. 18, 2013, now U.S. Pat. No.8,765,680; which is a continuation of U.S. application Ser. No.13/791,715, filed Mar. 8, 2013, now U.S. Pat. No. 8,653,033; which is acontinuation of U.S. application Ser. No. 13/616,607, filed Sep. 14,2012, now U.S. Pat. No. 8,513,198; which is a continuation applicationof U.S. application Ser. No. 13/176,568, filed Jul. 5, 2011, now U.S.Pat. No. 8,268,774; which is a continuation application of U.S.application Ser. No. 12/898,516, filed Oct. 5, 2010, now U.S. Pat. No.7,977,307; which is a continuation application of U.S. application Ser.No. 12/483,673, filed Jun. 12, 2009, now U.S. Pat. No. 7,833,973; whichis a continuation of U.S. application Ser. No. 11/831,702, filed Jul.31, 2007, now abandoned; which is a divisional application of U.S.application Ser. No. 10/956,252, filed Oct. 1, 2004, now U.S. Pat. No.7,268,109; which claims the benefit of U.S. Provisional Application Nos.60/508,625, filed Oct. 2, 2003, and 60/508,469, filed Oct. 3, 2003; theabove-identified applications are incorporated herein by reference intheir entirety.

FIELD OF THE INVENTION

The present invention relates to a method of providing analgesia fornociceptive and neuropathic pain by using a ω-conopeptide, such asziconotide, in combination with another pain drug.

BACKGROUND OF THE INVENTION

In general, although brain pathways governing the perception of pain arestill not completely understood, sensory afferent synaptic connectionsto the spinal cord, termed “nociceptive pathways” have been documentedin some detail. In the first part of such pathways, C- and A-fiberswhich project from peripheral sites to the spinal cord carry nociceptivesignals. Polysynaptic junctions in the dorsal horn of the spinal cordare involved in the relay and modulation of sensations of pain tovarious regions of the brain, including the periaqueductal grey region(μgeer, P. L., Eccles, J. C., and μgeer, E. G. (1987). MolecularNeurobiology of the Mammalian Brain, Plenum Press, New York). Analgesia,or the reduction of pain perception, can be effected directly bydecreasing transmission along such nociceptive pathways. Analgesicopiates are thought to act by mimicking the effects of endorphin orenkephalin peptide-containing neurons, which synapse at the C- orA-fiber terminal and inhibit release of neurotransmitters, includingsubstance P. Descending pathways from the brain are also inhibitory onC- and A-fiber firing.

Neuropathic pain is a particular type of chronic pain that has a complexand variable etiology. It is frequently a chronic condition attributableto complete or partial transection of a nerve, trauma or injury to anerve, nerve plexus or soft tissue, or other conditions, includingcancer, AIDS and idiopathic causes. Neuropathic pain is characterized byhyperalgesia (lowered pain threshold and enhanced pain perception) andby allodynia (pain from innocuous mechanical or thermal stimuli). Thecondition is progressive in nature. Because the hyperesthetic componentof neuropathic pain does not respond to the same pharmaceuticalinterventions as does more generalized and acute forms of pain,development of effective long-term treatment modalities has beenproblematic.

Opioid compounds (opiates) such as morphine, while effective inproducing analgesia for many types of pain, are not always effective,and may induce tolerance in patients. When a subject is tolerant toopioid narcotics, increased doses are required to achieve a satisfactoryanalgesic effect. At high doses, these compounds produce side effects,such as respiratory depression, which can be life threatening. Inaddition, opioids frequently produce physical dependence in patients.Dependence appears to be related to the dose of opioid taken and theperiod of time over which the drug is taken by the subject. For thisreason, alternate therapies for the management of chronic pain arewidely sought after. Compounds that serve as either a replacement for oras an adjunct to opioid treatment in order to decrease the dosage ofanalgesic compound required, have utility in the treatment of pain,particularly pain of the chronic, intractable type.

Although various types of calcium blocking agents, including a number ofL-type calcium channel antagonists and calcium chelators, have beentested as adjunct therapy to morphine analgesia, positive results areattributed to direct effects on calcium availability, since calciumitself is known to attenuate the analgesic effects of certain opioidcompounds (Ben-Sreti). EGTA, a calcium chelating agent, is effective inincreasing the analgesic effects of opioids. However, results from testsof calcium antagonists as adjunct therapy to opioids have beencontradictory. Some L-type calcium channel antagonists have been shownto increase the effects of opioids, while others of these compounds havebeen shown to decrease opioid effects (Contreras).

It is known to use omega-conopeptide to treat pain. For example, U.S.Pat. No. 5,051,403 describes the use of omega-conopeptides havingdefined binding/inhibitory properties in the treatment ofischemia-related neuronal damage. U.S. Pat. No. 5,364,842 demonstratesthe effectiveness of omega-conopeptide compositions in certain animalmodels of pain. Specifically, omega-conopeptides MVIIA and TVIA andderivatives thereof having related inhibitory and binding activitieswere demonstrated to produce analgesia in animal models of analgesia inwhich morphine is the standard positive control. PCT/US92/11349discloses that such conopeptides also produce relief from neuropathicpain, where morphine is not expected to produce positive results. U.S.Pat. No. 5,891,849 describes that omega-conopeptides are effective inpreventing progression of neuropathic pain.

U.S. Pat. No. 6,136,786 is directed to a method of enhancing theanalgesic effect produced by an opiate in a mammalian subject,comprising administering to the subject an effective dose of anomega-conopeptide having activity to (a) inhibit electrically stimulatedcontraction of the guinea pig ileum, and (b) bind to omega-conopeptideMVIIA binding sites present in neuronal tissue.

Wang and Bowersox (CNS Drug Reviews, 6(1): 2-20, (2000)) have reportedthe administration of ziconotide by intrathecal bolus injection withmorphine, clonidine, baclofen, bupivacaine in rats. Intrathecal bolusinjections of a combination of ziconotide and morphine dose-dependentlysuppress formalin-induced tonic flinch responses in rats. Intrathecalbolus injections of clonidine and ziconotide administered in combinationdose-dependently suppress tonic pain behavior in the rat hindpawformalin test. Administration of ziconotide and baclofen in combinationby intrathecal bolus injection produces additive analgesia in the rathindpaw formalin test. When co-administered with ziconotide byintrathecal bolus injection, bupivacaine (a sodium channel blocker) doesnot significantly alter ziconotide-induced analgesia in the formalintest.

Wang, et al. (Pain, 84: 271-281 (2000)) disclose that intrathecalinjections of ziconotide and morphine in rats (1 μg morphine+0.1 μgziconotide and 3 μg morphine+0.3 μg ziconotide) blocked acute phaseflinch responses following subcutaneous injection of formalin, whichwere significantly different from controls that received intrathecalbolus injection of 10 μl saline. The reference also discloses thatconcurrent infusion of intrathecal ziconotide (0.03 μg/hr) with morphine(15 μg/hr) for 7 days in rats produced marked antinociceptive responsesto noxious heat stimuli as measured by the hot-plate test or tailimmersion test during the first day of infusion. Thermal nociceptivethresholds thereafter declined toward the control level.

There is a need for an improved method of reducing pain in a humansubject. The improved method reduces the side effects of pain drugs, thenecessary doses of each drug, or the drug interactions.

SUMMARY OF THE INVENTION

The present invention is directed to a pharmaceutical formulationcomprising an ω-conopeptide and an analgesic compound selected from thegroup consisting of morphine, bupivacaine, clonidine, hydromorphone,baclofen, fentanyl citrate, buprenorphine, and sufentanil citrate, orits pharmaceutically acceptable salts thereof, wherein the ω-conopeptideretains its potency and is physically and chemically compatible with theanalgesic compound. A preferred ω-conopeptide is ziconotide. Thepharmaceutical formulation is suitable for intrathecal administration.

The present invention also provides a method for reducing pain. Themethod comprises the steps of administering to a subject an omegaconopeptide, preferably ziconotide, in combination with an analgesiccompound selected from the group consisting of morphine, bupivacaine,clonidine, hydromorphone, baclofen, fentanyl citrate, buprenorphine, andsufentanil citrate, or its pharmaceutically acceptable salts thereof,wherein the ω-conopeptide retains its potency and is physically andchemically compatible with the analgesic compound. A preferred route ofadministration is intrathecal administration, particularly continuousintrathecal infusion.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows (a) the mean percent change from baseline in VASPI scores(▪), and (b) mean Infumorph dose (o) for each week throughout the 4-weekcombination treatment phase.

FIG. 2 shows (a) the mean percent change from baseline in VASPI scores(▪), and (b) mean ziconotide dose (o) for each week throughout the5-week combination treatment phase.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a method of combination drugtherapy in which a patient is administered with a ω-conopeptide and oneor more other analgesic drugs. The ω-conopeptide and the other analgesicdrugs are co-administered by any of a number of routes ofadministration, particularly by intrathecal administration, andespecially by continuous intrathecal administration. This inventionfulfills a need for a method of dispensing analgesic drugs incombination with a ω-conopeptide so as to reduce the necessary doses ofeach drug in the combination, and so as to reduce the side effectsconcomitant to each analgesic. The combination administration ofanalgesic drugs with a ω-conopeptide also provides an additive, or evensynergistic effect in reducing pain in a subject.

The present invention provides a treatment method for reducingneuropathic pain in a human patient. The present invention is alsouseful in treating chronic pain such as that associated with cancer orAIDS. The method comprises administering to a subject an effectiveamount of an omega conopeptide, preferably ziconotide, combined with oneor more traditional analgesic compounds such as opioids, localanesthetics, adrenergic agonists, glutamate receptor antagonists, NMDAantagonists, and other analgesic agents.

Opioids suitable for the present invention include morphine,hydromorphone, fentanyl, fentanyl citrate, sufentanil, sufentanilcitrate, methadone, buprenorphine, and meperidine. Local anestheticsinclude bupivacaine, ropivacanine, and tetracaine. Adrenergic agonistsinclude clonidine and tizanidine. Glutamate receptor antagonists includedextrorphan, dextromethorphan, and memantine. NMDA antagonists includeketamine. Other analgesic agents include adenosine, aspirin, baclofen,droperidol, gabapentin, ketorolac, midazolam, neostigmine, octreotide (asomatostatin analogue), midazolam (a sedative/hypnotic) and valproate(an anti-epiliptic).

Omega Conopeptides

Omega conopeptides, also known as omega conotoxins, are a group of small(24-29 amino acids), disulfide-rich polypeptides, found in the venoms ofpredatory marine snails that belong to the genes Conus. Allω-conopeptides bind to N-type voltage sensitive calcium channels (VSCC),which are found exclusively in neurons, although the binding affinitiesfor specific VSCC subtypes may differ. In response to nerve cellmembrane depolarization, N-type VSCCs open and permit calcium entry thatresults in neurotransmitter release. N-type VSCCs are abundant in theRexed laminae I and II of the dorsal horn of the spinal cord, whereprimary afferent fibers in the pain signaling synapse for the firsttime. Omega conopeptides bind to N-type VSCCs in the Rexed laminae I andII and blocks calcium transport into the presynaptic terminal, therebyblocking neurotransmitter release. By blocking calcium entry at N-typeVSCCs in this location, pain signals, including those that develop afterperipheral nerve injury and characterize peripheral neuropathies, areless easily transmitted or are blocked completely.

A preferred omega conopeptide useful for this invention is ziconotide,which is available commercially as PRIALT™. Ziconotide (SNX-111), a25-amino acid peptide, is a synthetic version of a naturally-occurringpeptide found in the venom of the marine snail Conus magus. Ziconotidespecifically and selectively binds to VSCCs.

Omega-Conopeptides and Treatment of Chronic and Neuropathic Pain

Treatment with omega conopeptides, preferably ziconotide, is useful inpreventing progression of neuropathic pain. Analgesic omega-conopeptidesare effective as analgesic agents both in traditional opiate-sensitivemodels of nociceptive pain, such as the Rat Tail-Flick model or the ratformalin model, as well as in opiate-resistant models of pain, such asallodynia model of neuropathic pain.

Ziconotide has a unique combination of pharmacological actions.Specifically, intrathecally-administered ziconotide is more potent,longer acting, and more specific in its actions than are traditionalneuropathic pain targeting drugs such as morphine or clonidine.

Ziconotide are effective with intrathecal administration in animalmodels of acute, chronic, and neuropathic pain. Ziconotide, unlikemorphine, does not suppress respiratory function and does not haveaddiction potential. Once a therapeutic dose is reached, tolerance doesnot appear to develop as it does with opioids. Ziconotide are effectivein both non-neuropathic (visceral, somatic) and neuropathic cancer painand in non-malignant neuropathic pain states.

Stability of Ziconotide

Dilute solutions of omega-conopeptides are generally unstable insolution, as evidenced by oxidation of methionine residues and reductionor loss of biological activity. In particular, ziconotide, whichcontains a methionine at position 12, is approximately 10-fold lesspotent in binding to omega-conopeptide MVIIA binding sites when itsmethionine is present in the sulfoxy form. Omega-conopeptides can,however, be significantly stabilized in solution by preventing oxidationof methionine residues present in the peptide structure. Ziconotideoxidation, for example, can be prevented by addition of lactate bufferto the composition. More particularly, buffers containing 150 mM lactatebuffer, pH 4-4.5 improve stability of the compound considerably.Solutions of ziconotide in which the peptide concentration is less thanabout 0.1 mg/ml oxidize rapidly when dissolved in water, saline, or anyof a number of buffers used in the art of peptide chemistry. Solutionsof ziconotide ranging from 0.01-0.1 mg/ml are stable at 45° C. for weekswhen stabilized with lactate (150 mM, ph 4-4.5). Buffers containing 50μg/ml methionine are also effective in stabilizing ziconotide wheneither 150 mM lactate buffer or acidified saline (pH 4-4.5) is used tobuffer the solution.

Advantages of Combination Therapy with Omega Conopeptides and OtherAnalgesic Compounds

Combination therapy of omega conopeptides with other analgesic compoundsoffers several advantages over single drug administrations. First,administration of a combination drug therapy may allow dose reduction ofthe individual drug components, which reduces development of drugtolerance to either or both drugs, and reduces the likelihood of druginteractions. The reduced concentration of each drug also limits thedose dependent side effects of the drugs. In addition, the effectivedose (ED50) is reduced because a lower concentration of each drug isneeded to achieve therapeutic effect.

Second, the administration of a combination of two drugs, which utilizedifferent mechanisms to interrupt intractable or chronic painmechanisms, magnifies the beneficial effects of either or both drugs inan additive or synergistic fashion.

Third, intrathecal administration of ziconotide in combination withanother drug decreases or eliminates the usual sequelae of chronicintrathecal catheterization with morphine such as granuloma formation atthe catheter tip.

However, not all drugs are compatible in terms of stability andactivity. Ziconotide, when stored at μg/mL concentration, isparticularly subjected to interaction with other drugs in the admixture.For continuous intrathecal infusion, the admixture of drugs is stored at37° C. over a period of one week to a month or longer, it is importantthat ziconotide retains its activity over 80%, preferably over 90%during storage and administration.

Other Analgesic Compounds Morphine

Morphine (7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol) is anopium alkaloid that has potent analgesic properties toward all types ofpain. Morphine readily causes addiction, and is therefore a drug of lastresort when other pain-relieving drugs prove to be inadequate.INFUMORPH® (morphine sulfate) is a fairly stable salt prepared byneutralizing morphine with dilute sulfuric acid. Morphine sulfate doeslose water of hydration and darkens on exposure to air and light. Thismorphine salt is especially used in England by oral administration forthe management of pain in cancer patients. Typical intrathecal doses ofmorphine alone range between 0.5 and 75 mg/day, and usually between 2and 20 mg/day.

Hydromorphone

DILAUDID® (Hydromorphone Hydrochloride; dihydromorphinone hydrochloride)is a synthetic derivative of morphine prepared by the catalytichydrogenation and dehydrogenation of morphine under acidic conditionsusing a large excess of platinum or palladium. Hydromorphone is asubstitute for morphine (5 times as potent) but has approximately equaladdicting properties and a shorter duration of action. One advantage ofhydromorphone over morphine is that it gives less daytime sedation ordrowsiness. Typical daily dosages of hydromorphone range between 0.05and 15 mg/day.

Bupivacaine

MARCAINE® (Bupivacaine hydrocholoride) is a sodium channel blocker thatis used clinically both as a primary local anesthetic agent and as anadjuvant spinal analgesic. Bupivacaine is a local anesthetic of theamide class similar in chemical structure and properties tomeprivacaine. The duration of action of bupivacaine is 2 to 3 timeslonger than that of tetracaine. The potency of bupivacaine is comparableto tetracaine, but both are about 4 times that of mepivacaine andlidocaine. Typical intrathecal dosages of bupivacaine alone rangebetween 1 and 100 mg/day, usually between 5 and 15 mg/day.

Ropivacaine

Ropivacaine is an amide-type local anesthetic with a relative affinityfor A-delta and C fibers over A-beta fibers that makes it a choice foranalgesia without motor loss. Ropivacaine has less affinity for motorblockake with effective sensory blockade when compared to bupivacaine,and lower lipid solubility than buipvacaine. Compared to bupivacaine,ropivacaine is less toxic, more selective for sensory versus motornerves between the sensory and motor blockage, and has lowersolutibility resulting in greater spinal segmental spread. Compared tobupivacaine, ropivacaine has a shorter duration of action and biphasictime-dependent pharmacokinetics. (G. Bennett et al. (2000),Evidence-Based Review of the Literature on Intrathecal Delivery of PainMedication, Journal of Pain and Symptom Management, 20: S12-S11).

Clonidine

DURACLON (Hydromorphone;2,6-dichloro-N-2-imidazolidinylidenebenzenamine) is an antagonist at α₂adrenergic receptors, P₁ purinergic receptors, and H₂ histaminereceptors. Clonidine is used as a central antihypertensive drug and alsoabolishes most symptoms of opiate withdrawal. Clonidine is usedclinically to treat both acute (postoperative) pain and chronic painsyndromes. Known side effects of clonidine when used clinically for themanagement of pain include hypotension and bradycardia. Typical dailyintrathecal dosages of clonidine alone range between 10 and 400 μg,usually between 25 and 75 μg/day.

Baclofen

Baclofen (γ-amino-β-(p-chlorophenyl) butyric acid) is a 4-chlorophenylderivative of γ-aminobutyric acid (GABA) that acts as a selectiveagonist for the GABA_(B) receptor and inhibits the release of otherneurotransmitters in the central nervous system. Baclofen is used forits antispastic (muscle-relaxing) effects, and is especially indicatedfor intractable spasticity caused by spinal cord injury or multiplesclerosis. Baclofen also possess analgesic properties and isantinociceptive when administered parenterally or intrathecally in rats.The typical dosage range of baclofen alone for intrathecaladministration is 20-2000 μg/day, and usually 300-800 μg/day.

Fentanyl Citrate

SUBLIMAZE® (Fentanyl citrate; (N-(1-phenethyl-4-piperidyl)propionanilide citrate) is an anilide derivative with analgesic activity50 times that of morphine in man. Fentanyl Citrate is use primarily asan adjunct to anaesthesia, and has a rapid onset (4 minutes) and a shortduration of action. Side effects similar to those of other potentanalgesics are common-in particular, respiratory depression andbradycardia. Fentanyl citrate has dependence liability. Fentanyl istypically administered intrathecally at a dose of 10 μg/hour.

Sufentanil Citrate

Sufentanil citrate (N-[4-(methoxymethy)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide2-hydroxy-1,2,3-propanetricarboxylate) is a potent opioid analgesic.Sufentanyl is typically administered intrathecally at doses ranging from0.1 to 1.5 μg/hour.

Pharmaceutical Formulation

Formulations that comprise omega-conopeptides at various concentrationsin combination with any one or more of several drugs at variousconcentrations are envisioned, including but not limited to morphine,methadone, hydromorphone, buprenorphine, meperidine, fentanyl (e.g.fentanyl citrate), sufentanil (e.g. sufentanil citrate), bupivacaine,ropivacaine, tetracaine, clonidine, tizanidine, dextrorphan,dextromethorphan, memantine, ketamine, octreotide, valpreotide,baclofen, midazolam, neostigmine, aspirin, adenosine, gabapentin,ketorolac, octreotide, or droperidol, (or a pharmaceutically acceptablesalt thereof), wherein ziconotide retains its potency and is physicallyand chemically compatible with the analgesic compound.

The present invention is directed to a pharmaceutical formulationcomprising an ω-conopeptide and an analgesic compound selected from thegroup consisting of morphine, bupivacaine, clonidine, hydromorphone,baclofen, fentanil citrate, buprenorphine, and sufentanyl citrate, orits pharmaceutically acceptable salts thereof, wherein the ω-conopeptideretains its potency and is physically and chemically compatible with theanalgesic compound. A preferred ω-conopeptide is ziconotide. Thepharmaceutical formulation optionally comprises a pharmaceuticallyacceptable carrier.

The pharmaceutical formulation of the present invention is suitable forintrathecal administration, particularly continuous intrathecalinfusion. A preferred formulation is stable in a drug dispensingimplantable pump at 37° C. for at least 7 days.

Method for Reducing Pain

The present invention provides a method for reducing pain in a patient.The method comprises administering to a patient an effective amount ofan ω-conopeptide and an effective amount of an analgesic compound,wherein the ω-conopeptide and the analgesic compound are compatible andretain both activity during the administration. The ω-conopeptide andthe analgesic compound can each be in a separate formulation and beco-administered simultaneously or sequentially. Alternatively, theω-conopeptide and the analgesic compound can be pre-mixed and form oneformulation for administration.

The pharmaceutical formulation can be administered in a variety of ways,including but not limited to regionally or systemically, orally,parenterally, subcutaneously, intraperitoneally, intravascularly,perineurally, epidurally, and most particularly, intrathecally.Intrathecal delivery of drugs can be done by either a bolus injection ora continuous infusion. A bolus injection is defined as the injection ofa drug (or drugs) in a high quantity (called a bolus) at once, theopposite of gradual administration (as in intravenous infusion).Continuous infusion is defined as the administration of a drug or drugcombination over a prolonged period of time. The formulations may beformulated in a variety of ways, depending upon the manner ofintroduction. The dose of each drug in the drug formulation depends uponthe route of administration. Generally, dosages and routes ofadministration of the compounds are determined according to the site ofthe pain and the size of the subject, according to standardpharmaceutical practices.

A therapeutically effective dose is an amount effective to produce asignificant reduction in the chronic or neuropathic pain. The doselevels can sometimes be estimated, for new compounds, by comparison withestablished effective doses of known compounds with structuralsimilarities, taking into consideration predicted variations inbioavailability, biodistribution, and other pharmacokinetic properties,as can be empirically determined by persons skilled in the art. It iscontemplated that dosages of drugs used in combination drug therapy arethe same or lesser concentration than the concentration of each drugwhen administered alone by the same route of administration.

The combined drug formulation can be administered at any times after theonset of the neuropathic pain, or before an event known to elicitconditions of chronic or neuropathic pain.

In one embodiment of the invention, the method for reducing paincomprises the steps of administering to a patient an effective amount ofan ω-conopeptide and an effective amount of an analgesic compoundselected from the group consisting of hydromorphone, buprenorphine,fentanyl, and sufentanil, or its pharmaceutically acceptable saltsthereof. A preferred ω-conopeptide is ziconotide. A preferred route ofadministration is intrathecal administration, particularly continuousintrathecal infusion. The ω-conopeptide and the analgesic compound caneach be in a separate formulation and be co-administered simultaneouslyor sequentially. Alternatively, the ω-conopeptide and the analgesiccompound can be pre-mixed and form one formulation for administration.

In another embodiment of the invention, the method for reducing paincomprises the steps of administering to a patient an effective amount ofan ω-conopeptide and an effective amount of an analgesic compoundselected from the group consisting of bupivacaine, clonidine, andbaclofen, or its pharmaceutically acceptable salts thereof, wherein saidadministering is continuous intrathecal infusion. A preferredω-conopeptide is ziconotide. The ω-conopeptide and the analgesiccompound can each be in a separate formulation and be co-administeredsimultaneously or sequentially. Alternatively, the ω-conopeptide and theanalgesic compound can be pre-mixed and form one formulation foradministration.

In yet another embodiment of the invention, the method for reducing paincomprises the steps of administering to a patient intrathecally apharmaceutical formulation comprising a ω-conopeptide and morphine, orits pharmaceutically acceptable salts thereof. A preferredco-conopeptide is ziconotide. A preferred route of administration iscontinuous intrathecal infusion.

The present invention is also directed to a method for reducing pain ina patient susceptible to intrathecal opioid-induced granuloma formation.The method comprises intrathecally administering to the patient an omegaconopeptide. The method optionally further comprises administering tothe patient via continuous intrathecal infusion an effective amount ofan analgesic compound selected from the group consisting of bupivacaine,clonidine, and baclofen, or its pharmaceutically acceptable saltsthereof.

The invention is illustrated further by the following examples that arenot to be construed as limiting the invention in scope to the specificprocedures described in it.

EXAMPLES Example 1. Stability of Ziconotide

Objectives:

Ziconotide drug product is currently formulated at 100 μg/mL in saline,pH adjusted to 4.3. Free methionine (50 μg/mL) is added to the solutionas an antioxidant. This solution has demonstrated excellent stabilitywhen stored at 2-8° C. for three years. When this material is used inclinical trials, physicians frequently dilute the drug product to 25μg/mL, using silane. This reduces the concentration of free methioninefour-fold, and subjects the peptide to additional oxidative degradation.The objective of this study is to investigate the stability of a 25μg/mL Ziconotide solution in 50 μg/mL methionine.

To investigate the feasibility of manufacturing a 25 μg/ml ziconotide in50 μg/ml methionine, stability profiles of 25 μg/ml were generated froman accelerated stability study at 25° C., 40° C., and 60° C. atpre-determined time points.

To prepare 25 μg/ml ziconotide solution, dilutions were performed in aglove box attached to a nitrogen gas source to ensure an oxidative-freeenvironment. 255 ml of L-methionine/sodium chloride solution (50 μg/mlL-methionine) was measured and transferred to 500 ml storage bottles. 85ml of ziconotide REF007 (100 μg/ml) was added to the storage bottle,which was then closed tightly and stirred for a minimum of 5 minutes,after which pH was determined. If pH was outside the range of 4.25 to4.35, pH was adjusted with the addition of 0.15N NaOH or 0.15N HCl tobring it within the range. The solution was then aliquoted at 20 ml pervial. Vials were capped with rubber stoppers and an aluminum seal. Vialswere stored at 5° C., 25° C., 40° C., or 60° C.

The stability of the ziconotide formulation was analyzed for percentlabel claim at 4 temperatures (5° C., 25° C., 40° C., or 60° C.), andwas tested in fresh vials at each temperature at day 0, 1 month, 2months, and 3 months post dilution. At each test, appearance and pH wereassessed. In addition, RP-HPLC was used to identify, concentrate, andpurify each sample. Arrhenius analysis (assuming linearity) wasconducted to estimate stability as a function of time at 5° C. Throughthe Arrhenius Plot Analysis, the ziconotide formulation (25 μg/ml) isestimated to meet label requirements (>90%) for approximately 4442months (approximately 370 years).

Example 2. Compatibility of Ziconotide with Other Intrathecal DrugsPhysical Compatibility

The physical compatibility of the ziconotide with 7 other currentlymarketed intrathecal drugs (Hydromorphone HCL, Bupivacaine HCL, MorphineSulfate Injection, Fentanyl Citrate Injection, sufentanil citrate,Baclofen for Injection, and Clonidine HCL for Injection) was determinedby evaluating appearance, color, pH, and particulate matter beforemixing and 24 hours after mixing in admixture. In order to be consideredphysically compatible, admixture solutions must have met the USPcriteria for particulates, must remain within acceptable pH, and musthave no changes in color or appearance.

100 μg of Ziconotide was mixed with each drug in a 1:8 and a 8:1ziconotide to drug volume ratio. Data from this study is listed in Table1 below:

TABLE 1 Physical Compatibility Ratio Ziconotide:Second PhysicalZiconotide Admixture Drug Compatibility Hydromorphone HCl, 2 mg/mL 1:8Yes (Dilaudid HP) Hydromorphone HCl, 2 mg/mL 8:1 Yes (Dilaudid HP)Bupivacaine HCl, 7.5 mg/mL 1:8 Yes (Marcaine Spinal) Bupivacaine HCl,7.5 mg/mL 8:1 Yes (Marcaine Spinal) Morphine sulfate, 25 mg/mL 1:8 Yes(Infumorph 500) Morphine sulfate, 25 mg/mL 8:1 Yes (Infumorph 500)Morphine Sulfate Injection, 1:8 Yes 1 mg/mL Morphine Sulfate Injection,8:1 Yes 1 mg/mL Fentanyl Citrate Injection, USP 1:8 Yes 0.05 mg/mLFentanyl Citrate Injection, USP 8:1 Yes 0.05 mg/mL Sufenta Injection0.05 mg/mL 1:8 Yes (Sufentanil citrate) Sufenta Injection 0.05 mg/mL 8:1Yes (Sufentanil citrate) Sufentanil Citrate Injection 1:8 Yes 0.05 mg/mLSufentanil Citrate Injection 8:1 Yes 0.05 mg/mL Baclofen for Injection,2 mg/mL 1:8 Yes (Lioresal Intrathecal) Baclofen for Injection, 2 mg/mL8:1 Yes (Lioresal Intrathecal) Clonidine HCl for Injection, 1:8 Yes 0.1mg/mL (DURACLON) Clonidine HCl for Injection, 8:1 Yes 0.1 mg/mL(DURACLON)

Chemical Compatibility

The chemical compatibility of ziconotide with 5 other intrathecal drugswas determined by evaluating the ziconotide concentration while inadmixture, by High Performance Liquid Chromatography (HPLC). Theprepared admixtures were stored in polymethylpentene vials at 37° C. fora period of 60 days. Ziconotide diluted to 0.025 mg/ml with 0.9% SodiumChloride for Injection, USP, was combined with each drug at a high andlow concentration. The concentration of the other component in theadmixture was not determined. Data from this study is presented below inTable 2.

TABLE 2 Chemical Compatibility Ziconotide Ziconotide Stability Stability(Days (Days Admixed Drug (Concentration) above 90%) above 80%)Hydromorphone HCl (2 mg/mL) 32 days 46 days Hydromorphone HCl (10 mg/mL) 3 days 13 days Morphine sulfate (5 mg/mL) 13 days 32 days Morphinesulfate (25 mg/mL)  3 days 13 days Fentanyl citrate (0.05 mg/mL) 39 days60 days Fentanyl citrate (0.10 mg/mL) 39 days 60 days sufentanil citrate(0.01 mg/mL) 60 days 60 days sufentanil citrate (0.05 mg/mL) 60 days 60days Clonidine HCl (0.5 mg/mL) 60 days 60 days Clonidine HCl (3.0 mg/mL)60 days 60 days

Example 3. Compatibility of Ziconotide and INFUMORPH® (Morphine Sulfate)in the Medtronic SYNCHROMED® Infusion System

The compatibility of ziconotide when mixed with morphine sulfate wasdetermined by mixing 100 μg/ml of ziconotide with morphine sulfate(INFUMORPH®), and placing the admixture into a Medtronic SYNCHROMED®Infusion system (a drug dispensing implantable pump). Samples wereobtained from the pump reservoir at specified intervals, and theconcentrations of both drug components in the admixture were determined.Table 3 shows the stability of ziconotide, which is expressed as apercentage of the initial concentration of ziconotide.

TABLE 3 Ziconotide Ziconotide Stability Stability Ziconotide:INFUMORPH ®(Days (Days Volume Ratio above above Admixed Drug (final concentration)90%) 80%) INFUMORPH 1:3 7 days 28 days 200 (10 mg/mL)  (25 μg/mL:7.5mg/mL) INFUMORPH 1:9 14 days  28 days 200 (10 mg/mL) (10 μg/mL:9 mg/mL) INFUMORPH 1:3 0 days  0 days 500 (25 mg/mL)   (25 μg/mL:22.5 mg/mL)INFUMORPH 1:9 7 days 14 days 500 (25 mg/mL)   (10 μg/mL:18.75 mg/mL)

On average, the concentration of morphine sulfate remained above 90% ofinitial concentration in all admixtures for 60 days.

The pH of the admixtures remained within 1.0 pH unit of initial pH,ranging from 4.2 to 4.8. The appearance of the solutions did not changesignificantly, although a slight yellow color was observed in admixturescontaining INFUMORPH® 500.

Example 4. Morphine and Ziconotide Interactions—Analgesic Activity ofConcomitantly Administered Morphine and Ziconotide Synergistic Effect ofConcomitantly Administered Morphine and Ziconotide (Hot-Plate and TailImmersion Tests)

Continuous, intrathecal infusions of 0.03 μg/hr ziconotide produce, atmost, modest increases in thermal (heat) response latencies in the rathot-plate and tail immersion tests. However, when 0.03 μg/hr ziconotideis co-administered with moderately antinociceptive doses of morphine (15μg/hr), response latencies in both tests greatly exceed those producedby either compound alone.

Additive Effect of Concomitantly Administered Morphine and Ziconotide(Formalin Test)

In the rat hindpaw formalin test, intrathecal bolus injections of acombination of ziconotide and morphine in a fixed dose ratio of 1:10,dose-dependently suppress formalin-induced tonic flinch responses. Themeasured ED₅₀ value is not significantly different from the valuepredicted by assuming additive analgesic effects. This observationsuggests that morphine and ziconotide administered concomitantly in thismodel produce additive analgesic effects.

Our results show that intrathecal co-administration of ziconotide andmorphine has a synergistic effect on analgesia in rat models of acutethermal nociception but has additive effects in a rat model ofpersistent pain (formalin test).

Tolerance to Ziconotide and/or MorphineStudies in rats have shown that:

-   -   Ziconotide does not prevent the development of tolerance to the        analgesic effects of morphine.    -   Ziconotide has no effect on morphine-induced analgesia in        morphine-tolerant rats.    -   Subacute intrathecal infusion of ziconotide does not influence        subsequent morphine analgesia.

The ability of ziconotide to affect the development of tolerance to theanalgesic effects of morphine has been investigated using two rat modelsof acute pain: the hot plate test and the tail immersion test. Theanalgesic effects of morphine (15 μg/hr) administered by continuousintrathecal infusion declined in magnitude (i.e., tolerance develops)during subacute administration; after five days of a seven day morphineinfusion, evoked pain behavior is comparable to that exhibited bysaline-treated controls. Ziconotide (0.03 μg/hr) and morphine (15 μg/hr)administered in combination did not prevent this observed decline in theanalgesic efficacy of morphine.

The ability of ziconotide to reverse morphine tolerance has beenevaluated in the rat paw formalin test. Rats given intrathecal bolusinjections of ziconotide (0.03 μg/hr) in combination with morphine (20μg/hr) three hours after completion of seven days of continuous,constant-rate intrathecal morphine (15.18 μg/hr) infusions hadpost-formalin injection flinch counts equivalent to those observed inmorphine-naive animals given ziconotide alone. These findings indicate:

-   -   1. Ziconotide does not restore the analgesic efficacy of        morphine when it is administered to morphine-tolerant animals.    -   2. Rats tolerant to the analgesic effects of        intrathecally-administered morphine do not exhibit        cross-tolerance to ziconotide.

Subacute (six days) intrathecal infusion of ziconotide does notinfluence morphine-induced analgesia in the rat hindpaw formalin test(Omote, et al.). Intrathecal infusion of 0.005 μg/hr ziconotide for sixdays produced moderate, but not statistically significant, reductions intonic formalin-induced flinching behavior. An intrathecal bolusinjection of 1 μg morphine administered to animals pretreated for sixdays with intrathecal infusions of saline significantly reduced tonicflinch responses; the same dose of morphine produced slightly greaterinhibition of tonic flinch behavior in rats that received intrathecalinfusions of 0.005 μg/hr ziconotide for six days immediately precedingmorphine treatment. These observations show that subacute intrathecalinfusion of ziconotide does not reduce or prevent morphine-inducedanalgesia. In addition, these results are consistent with other findingsindicating that acute intrathecal injection of ziconotide and morphineproduces additive analgesic effects in the rat hindpaw formalin test.

Example 5. Behavioral and Cardiovascular Responses to ConcomitantlyAdministered Morphine and Ziconotide

Acute interactions between morphine administered subcutaneously (10 or30 mg/kg) and ziconotide (0.1 μg) administered by intrathecal bolusinjection were examined in rats using a conventional functionalobservational battery and measurements of heart rate and blood pressure.Gross behavioral and cardiovascular effects of SC morphine andintrathecal bolus injections of ziconotide were neither potentiated nordiminished when the compounds were administered concurrently. Thesefindings indicate that analgesic doses of ziconotide are well toleratedwhen given intrathecal, either alone or in combination with high dosesof SC morphine.

Example 6. Respiratory Effects of Concomitantly Administered Morphineand Ziconotide

Intrathecal administration of ziconotide did not depress respiratoryminute volume responses to CO₂ inhalation in rats nor did it exacerbateacute respiratory depression induced by SC injections or morphine.Intrathecal bolus injection of ziconotide, at a dose (0.1 μg) thatproduces marked analgesia with minimal side effects did not depressrespiratory minute volume responses to CO₂, nor did it exacerbate acuterespiratory depression induced by SC bolus injection of morphine (10 or30 mg/kg). Similarly, analgesic doses of ziconotide, administeredsubacutely by continuous intrathecal infusion (0.1 or 0.3 μg/hr), eitheralone or in combination with an analgesic dose of subcutaneouslyadministered morphine (200 μg/hr), did not induce respiratorydepression.

Ziconotide did not induce morphine-tolerant rats to become moresensitive to the respiratory depressant effects of morphine. Respiratoryminute volume responses to CO₂ inhalation were comparable to controlvalues when rats, made tolerant to the respiratory-depressant propertiesof morphine by SC injection of 10 mg/kg morphine twice daily for sevendays, were given intrathecal injections of 0.1 μg ziconotide 30 minutesbefore a morphine challenge.

These findings confirm that ziconotide neither produces respiratorydepression nor restores sensitivity to the respiratory-depressantproperties of morphine when it is administered intrathecally tomorphine-tolerant animals.

Example 7. Gastrointestinal Effects of Concomitantly AdministeredMorphine and Ziconotide

In rats, morphine administered by SC bolus injection produced adose-dependent inhibition of GI transit. When morphine was administeredin combination with an intrathecal dose of ziconotide (0.3 μg) that doesnot itself affect GI tract motility, the morphine does-response curvewas shifted significantly to the left. This finding indicates thatziconotide and morphine interact synergistically to reduce GI transit inrats. In contrast, when mice were given a SC injection of morphine (3mg/kg) together with an intrathecal dose of ziconotide (1 μg),gastrointestinal transit was reduced to an extent similar to thatobserved when morphine was administered alone. This finding does notconclusively exclude a potential interaction between the two compounds,because of the possibility that GI transit may have been maximallyreduced by one or the other compound when administered alone.

Example 8. Analgesic Activity of Concomitantly Administered Baclofen andZiconotide

Baclofen, a selective GABA_(B) receptor agonist, is indicated for spinaluse in the treatment of intractable spasticity caused by spinal cordinjury or multiple sclerosis. Baclofen also possesses analgesicproperties and is antinociceptive when administered by either parenteralor intrathecal routes in laboratory animals. In rats, intrathecal bolusinjections of baclofen or ziconotide alone led to dose-dependentreductions in persistent pain behavior evoked by SC injection of 5%formalin into the dorsal hindpaw. When ziconotide and baclofen wereadministered in combination by intrathecal bolus injection, the effecton formalin-induced tonic pain behavior was statistically equivalent tothe sum of the effects produced by each compound administered alone.These results indicate that concomitant intrathecal administration ofziconotide and baclofen produces additive analgesia in the rat hindpawformalin test.

Example 9. Analgesic Activity of Concomitantly Administered Bupivacaineand Ziconotide

Bupivacaine is a sodium channel blocker that is used clinically both asa primary local anesthetic agent and as an adjuvant spinal analgesic.Intrathecal bolus injections of bupivacaine did not significantlyinhibit formalin-induced acute or persistent hindpaw flinching behavior,however, 300 μg bupivacaine produced immediate but transient hindpawparalysis. Intrathecal bolus injections of ziconotide (0.03, 0.1, or 0.3μg) suppressed persistent pain behavior in a dose-dependent manner. Whenco-administered with ziconotide by intrathecal bolus injection,bupivacaine, administered in doses that did not produce complete nerveblock, did not significantly alter ziconotide-induced analgesia. Theresults suggest that bupivacaine neither produces analgesia nor altersziconotide-induced analgesia in the rat hindpaw formalin test.

Example 10. Analgesic Activity of Concomitantly Administered Clonidineand Ziconotide

Clonidine, an α₂-adrenoceptor agonist, produces analgesia viacentrally-mediated mechanisms when it is administered or systemically.Clonidine is used clinically to treat both acute (postoperative) painand chronic pain syndromes. Intrathecal bolus injections of clonidine orziconotide, administered alone or in combination, dose-dependentlysuppressed tonic pain behavior in the rat hindpaw formalin test. Thetheoretical additive ED₅₀ for the drug combination is not significantlydifferent from the observed value nor is there a significant differencebetween the regression lines fitted to the log linear portions of thecomposite additive and mixture dose-response curves. These findingssupport the conclusion that ziconotide and clonidine have additiveanalgesic effects when concomitantly administered by the intrathecalroute.

Example 11. Cardiovascular Responses of Concomitantly AdministeredClonidine and Ziconotide

Clonidine has known side effects of hypotention and bradycardia whenused clinically for the management of pain. In rats, clonidine deliveredby intrathecal bolus injection produced dose-dependent bradycardia andhad dual effects on arterial blood pressure: low doses (1-3 μg) producedCNS-mediated hypotension, whereas high doses (10-50 μg) produced markedpressor responses due to the activation of peripheral α₂-adrenoceptorsin vascular smooth muscle. An intrathecal bolus injection of a highanalgesic dose of ziconotide (0.3 μg), administered 10 minutes prior toclonidine injection, did not exacerbate the depressor or bradycardiaresponses elicited by intrathecal clonidine (3 μg) in conscious rats,indicating the absence of a significant drug interaction within thecardiovascular system.

Example 12. Continuous Intrathecal Infusion of Ziconotide in Rat SandDogs

The potential toxicity of ziconotide was evaluated by continuousintrathecal infusion for 28 days at doses in rats up to 1500 ng/kg/hrand in dogs up to 1200 ng/kg/hr; at least 30-fold the highest expecteddose in patients.

Mean plasma drug levels measured in high-dose rats and dogs wereapproximately 3 and 10-fold greater than human, respectively, althoughoverall systemic exposure to ziconotide was low (<4 ng/ml). Expectedtreatment-related pharmacological effects on the CNS, consisting mainlyof tremors, shaking-behavior and/or ataxia, were of sufficient severityin dogs to require moribund euthanasia in 4/16 animals ≥600 ng/kg/hour.There were no treatment-related changes in body weight, food intake orclinical pathology parameters nor was any target organ toxicityidentified in either species at termination. Neurohistopathologicexaminations revealed spinal cord compression with associated chronicinflammation in control and ziconotide-treated rats and dogs, which wasattributed to pressure exerted by the IT catheter. This finding was notexacerbated with ziconotide exposure and no other histopathologicchanges were observed. In conclusion, behavioral and neurologicaleffects observed in rats and dogs receiving 28-day continuous ITinfusions of ziconotide appeared related to the pharmacological activityof ziconotide with no associated neurotoxicity or histopathology.Further, no granuloma formation at the catheter tip was observed inziconotide-treated dogs when infusion site tissue sections wereexamined, as has been reported with IT morphine administration (Yaksh,et al., Anesthesiology 2003; 99:174-87).

Example 13. Clinical Study of Combined Intrathecal Infusion ofZiconotide (Constant Dose) and Morphine (Increasing Dose) PatientCriteria

The patient population included male and female patients on a stabledose of intrathecal (IT) ziconotide. The patients all had been on a doseof ziconotide of at least 0.2 μg/hr (4.8 g/day). In addition, thepatients either had sub-optimal pain relief demonstrated by a VisualAnalog Scale of Pain Intensity (VASPI) score of ≥40 mm, or had residualpain not relieved by ziconotide and of a different nature than the painrelieved by ziconotide.

Ziconotide

Ziconotide was supplied at a concentration of 100 μg/mL in 5 mL singledose vials. The ziconotide dose was at least 0.2 μg/hr (4.8 μg/day). Themean dose of ziconotide during the 4-week treatment phase ranged from26.5 μg/day at week 1 to 27.9 μg/day at week 4. The mean cumulative doseof ziconotide at termination was 731.1 μg. Patients were exposed toziconotide for a mean duration of 27 days (range=3 to 30 days) duringthe 4-week combination treatment phase.

Morphine

Infumorph (preservative-free morphine sulfate sterile solution; ElkinsSinn, Inc., Cherry Hill, N.J.) was supplied in 20 mL glass ampules at amorphine concentration of either 10 or 25 mg/mL. The Infumorph doseescalation schedule was adjusted according to the individual patient'sdaily dose of systemic opiates. In the low dose regimen, patientsreceiving less than 100 mg/day oral morphine equivalents started at 0.25mg/day and the dose was escalated to 0.5, 1.0, and 2.0 mg/day on weeks2, 3, and 4, respectively. In the medium dose regimen, patientsreceiving 100-300 mg/day of oral morphine equivalents started at 0.5mg/day, and the dose was escalated to 1.0, 2.0, and 3.0 mg/day on weeks2, 3, and 4, respectively. In the high dose regimen, patients receivingover 300 mg/day of oral morphine equivalents started at a dose of 1.0mg/day, and the dose was escalated to 2.0, 3.0, and 4.0 mg/day on weeks2, 3, and 4, respectively. The dose escalation of Infumorph was stoppedif intolerable adverse events occurred or significantly improvedanalgesia was obtained.

Patients were initiated on Infumorph in combination with IT ziconotideat the initial visit. Infumorph was initiated at a mean dose of 0.44mg/day during week 1 of the study and increased weekly thereafter. MeanInfumorph doses were 0.80 mg/day, 1.41 mg/day, and 2.06 mg/day duringweeks 2, 3, and 4 of treatment, respectively. The mean cumulative doseof Infumorph at termination was 31.1 mg (range: 1.3 to 71.0 mg). Onaverage, patients were exposed to Infumorph for a total duration of 27days (range: 3 to 30 days).

Efficacy Analysis

Efficacy measurements included the VASPI score, Categorical Pain ReliefScale (CPRS), Clinical Global Impression (CGI), and Weekly SystemicOpioid Consumption.

Statiscal Efficacy Analysis

For the assessment of the efficacy of combined intrathecal ziconotideand morphine, patients rated their current pain intensity using theVisual Analog Scale of Pain Intensity (VASPI), Handbook of PainAssessment (2nd Edition), D. C. Turk and R. Melzack, Eds, GuilfordPress, new York, 2001. For the baseline evaluation, patients rated theircurrent pain intensity on a 100-mm line representing the pain continuum(i.e., from “No Pain” to “Worst Possible Pain”). The left side of thecontinuum corresponds to a numerical score of 0 and the right side ofthe continuum corresponds to a numerical score of 100. At each studyvisit, the patient was asked to rate his/her current pain intensityusing the same continuum described above. The primary pain efficacyevaluation for the trial was the percent change in VASPI while oncombination therapy compared with the baseline measurement while on asingle intrathecal analgesic (ziconotide).

Summary of Results

A total of 24 patients participated in the testing. Twenty-two (92%)patients completed the 4-week treatment phase and two (8%) patientsdiscontinued treatment prematurely due to an adverse effect.

At the initial visit, VASPI scores ranged from 42 to 100 mm (n=24,mean=70.7 mm). All patients suffered from non-malignant pain, which wasclassified as neuropathic (n=20, 83%), nociceptive (n=10, 42%) ordegenerative (n=9, 38%). Patients had suffered with pain for an averageduration of 14.8 years, ranging from 4 to 40 years. All patients wererefractory to pain treatment (n=24, 100%). In addition, ten patients(42%) had failed back surgery syndrome.

The primary efficacy measure (VASPI) was assessed weekly throughout the4-week combination treatment phase. FIG. 1 shows (a) the mean percentchange from baseline in VASPI scores (▪), and (b) mean Infumorph dose(∘) for each week throughout the 4-week combination treatment phase. Onaverage, a reduction in pain intensity was observed at each week. WeeklyVASPI reductions corresponded with increased Infumorph doses throughoutthe 4-week treatment phase. The mean percent reduction in VASPI scoreswas 11.3% after one week of combination therapy and 26.1% after fourweeks of combination therapy when compared with baseline measurement ona single ziconotide treatment.

Example 14. Clinical Study of Combined Intrathecal Infusion of Morphine(Constant Dose) and Ziconotide (Increasing Dose) Patient Criteria

The patient population included male and female patients on a dose of ITmorphine ranging between 2 and 20 mg/day. Patients either hadsub-optimal pain relief demonstrated by a Visual Analog Scale of PainIntensity (VASPI) score of ≥40 mm, or had residual pain not relieved bymorphine and of a different nature than the pain relieved by morphine(e.g., neuropathic pain).

Ziconotide

Ziconotide was supplied at a concentration of 100 μg/mL in 5 mL singledose vials. Ziconotide doses increased weekly throughout the treatmentphase of the study, starting at 0.025 μg/hour (0.6 μg/day) at baseline.Patients were seen weekly thereafter and received increased ziconotidedose as follows: 0.05 μg/hr (1.2 μg/day) at Visit 2 (Day 7), 0.10 μg/hr(2.4 μg/day) at Visit 3 (Day 14), 0.20 μg/hr (4.8 μg/day) at Visit 4(Day 21), and 0.30 μg/hr (7.2 μg/day) at Visit 5 (Day 28). The doseescalation of ziconotide was stopped if intolerable adverse eventsoccurred, significantly improved analgesia was obtained, or if the finaldose of 0.30 μg/hr was reached. The mean cumulative dose of ziconotideat termination was 74.4 μg (range: 8.8 to 118.6 μg), and the mean doseduring week 5 was 0.197 μg/mL. On average, patients were exposed toziconotide for a total duration of 31.5 days (range: 14 to 35 days).

Morphine

Infumorph (preservative-free morphine sulfate sterile solution; ElkinsSinn, Inc., Cherry Hill, N.J.) was supplied in 20 mL glass ampoules at amorphine concentration of either 10 or 25 mg/mL. The Infumorph doseremained stable throughout the combination treatment phase of the studyand ranged between 2 and 20 mg/day.

All patients (n=22) were receiving IT Infumorph therapy at the screeningvisit at a mean dose of 12.3 mg/day (range: 2.0 to 20.0 mg/day).Subsequently, patients were stabilized on IT Infumorph monotherapy at amean dose of 12.4 mg/day (range: 1.8 to 20.0 mg/day) for an averageduration of 8.8 days prior to receiving combination IT Infumorph andziconotide therapy at the baseline visit. The mean dose of Infumorphduring the 5-week treatment phase ranged from 12.4 mg/day at week 1 to12.7 mg/day at week 5. Patients were exposed to Infumorph for a meanduration of 40.7 days (range=25 to 56 days) during the screening and5-week combination treatment phases.

Efficacy Analysis

Efficacy measurements included the VASPI score, Categorical Pain ReliefScale (CPRS), Clinical Global Impression (CGI), and Weekly SystemicOpioid Consumption.

Statistical Efficacy Analysis

For the assessment of the efficacy of combined intrathecal ziconotideand morphine, patients rated their current pain intensity using theVisual Analog Scale of Pain Intensity (VASPI), as described in Example13. The primary pain efficacy evaluation for the trial was the percentchange in VASPI while on combination therapy compared with the baselinemeasurement while on a single intrathecal analgesic (morphine).

Summary of Results

A total of 22 patients participated in the testing. Sixteen (73%)patients completed the 5-week treatment phase and six (27%) patientsdiscontinued treatment prematurely due to an adverse effect.

At screening, VASPI scores ranged from 41 to 91 mm (mean=66.6 mm). Onaverage, pain intensity increased from the screening visit to thebaseline visit (mean=71.7 mm). All patients suffered from non-malignantpain, which was classified as neuropathic (n=16, 73%) or mixed (n=13,59%). Patients had suffered with pain for an average duration of 9.6years, ranging from 2.5 to 40 years. In addition, the majority ofpatients (n=20, 91%) had failed back surgery syndrome and wererefractory to pain treatment.

The primary efficacy measure (VASPI) was assessed weekly throughout the5-week combination treatment phase. FIG. 2 shows (a) the mean percentchange from baseline in VASPI scores (▪), and (b) mean ziconotide dose(∘) for each week throughout the 5-week combination treatment phase. Onaverage, a reduction in pain intensity was observed at each week throughweek 5. Weekly VASPI reductions corresponded with increased ziconotidedoses throughout the 5-week combination phase with the exception of thefinal dose increase at week 5 (see FIG. 2). The mean percent reductionin VASPI scores was 2.7% after one week of combination therapy and 21.4%after 5 weeks of combination therapy.

Example 15. Clinical Study Protocol of Combined Intrathecal Infusion ofBaclofen (Constant Dose) and Ziconotide (Increasing Dose) PatientCriteria

The patient population includes male and female patients on a dose of ITbaclofen (either compounded baclofen or LIORESAL®) ranging between 22and 800 μg/day. Patient has pain and sub optimal pain relief indicatedby a minimum VASPI of 40 mm at the Screening and Baseline Visit.

Visit 1/Baseline Visit (Day 0)

All patients must be on stable doses of LIORESAL® (between 22 and 800μg/d), systemic opioids, and other concomitant medications for at least7 days prior to the Baseline Visit. The contents of the SynchroMed® ELInfusion System are removed and replaced with PRIALT™ and LIORESAL®. TheLIORESAL® dose remains the same as during the last 7 days of thescreening period and throughout the first 9 weeks of the trial. Theinitial dose of PRIALT™ is 0.025 μg/hr (0.6 μg/d).

PRIALT™

The initial PRIALT™ dose is 0.025 μg/hr (0.6 μg/d) for one week startingat Baseline (Day 0). After one week of treatment, the pump is refilledand the dose increased to 0.05 μg/hr (1.2 μg/d). After the third week oftreatment, the pump is refilled and the dose increased to 0.10 μg/hr(2.4 μg/d). After five weeks of treatment, the pump is refilled and thedose increased to 0.15 μg/hr (3.6 μg/d). After seven weeks of treatment,the pump is refilled and the dose increased to 0.20 μg/hr (4.8 μg/d).During the final week, the dose will be maintained at 0.20 ag/hr (4.8μg/d). Dose increases are made until an Escalation Stopping Criterion isencountered.

LIORESAL®

The LIORESAL® dose is kept constant and unchanged from the stable doseestablished during screening and is at least 22 μg/day and no more than800 μg/day.

Pump Flow Rate

The pump flow rate is held constant and is at least 12 mcl/hr (288mcl/d) to allow for clearance of the pump volume within one or two days.Drug dosage is not to be adjusted by changing the pump flow rate as thiswould change the rate of infusion of both compounds.

Pain Measurement

Visual Analog Scale of Pain Intensity (VASPI) is determined at eachclinic visit. Categorical Pain Relief Scale (CPRS) is determined atVisit 7/Early Termination and Extension Phase Termination Visit ifapplicable. Clinical Global Impression (CGI) is determined at Visit7/Early Termination and Extension Phase Termination Visit if applicable.

Other Clinical Measurements

Spasticity scales (Modified Ashworth Scale: 0-4 normal to rigid tone;Spasm Scale 0-4 no spasms to greater than 10 per hr; Penn SpasmFrequency Scale, Visual Analogue of Spasticity Scale or VASS) isdetermined at each clinic visit.

Efficacy Variables

Primary Efficacy Variable includes: Percentage change in VASPI scoresfrom the Baseline Visit to Visit 7/Early Termination Visit.

Secondary Efficacy Variables Include:

Percentage change in VASS scores from the Baseline Visit to Visit7/Early Termination Visit.

Change in VASPI and VASS scores from the Baseline Visit to Visit 7/EarlyTermination.Percentage change and change in VASPI and VASS scores from the BaselineVisit to each of Visits 2-6.

Distribution of CPRS at Visit 7/Early Termination Visit. Distribution ofCGI at Visit 7/Early Termination Visit.

Change and percent change in weekly systemic opiate consumption.Change and percent change in weekly oral baclofen consumption.Spasticity scale changes.

The invention, and the manner and process of making and using it, arenow described in such full, clear, concise and exact terms as to enableany person skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the scope of the present invention as setforth in the claims. To particularly point out and distinctly claim thesubject matter regarded as invention, the following claims conclude thisspecification.

What is claimed is:
 1. A method for treating severe chronic pain in ahuman patient, comprising: administering ziconotide to a human patientsuffering from severe chronic pain by continuous intrathecal infusionwith a dose starting at 0.6 μg/day, titrating upward by up to 2.4 μg/dayper week, and up to a maximum of 7.2 μg/day or until a significantlyimproved analgesia is obtained.
 2. The method according to claim 1,wherein the patient is treated for 14-35 days.
 3. The method accordingto claim 1, wherein the cumulative dose of the ziconotide is 8.8-118.6μg.
 4. The method according to claim 1, wherein said ziconotide isadministered in a pharmaceutical composition comprising an antioxidant.5. The method according to claim 4, wherein said antioxidant ismethionine.
 6. The method according to claim 4, wherein saidpharmaceutical formulation has pH between 4 and 4.5.
 7. The methodaccording to claim 4, wherein said ziconotide is supplied in a singledose vial.
 8. The method according to claim 7, wherein said ziconotidehas a concentration of 100 μg/mL in the vial.
 9. The method according toclaim 4, wherein the ziconotide is administered via a drug dispensingimplantable pump.
 10. The method according to claim 1, wherein the humanpatient is being administered a therapeutically effective amount of anopioid.